5-Lipoxygenase (hereinafter referred to as 5-LO) is an enzyme involved in an arachidonic acid metabolism which synthesizes leukotriene by acting on the generatation of 5-HPETE from the arachidonic acid. LTB4, the most powerful chemottractant among thus synthesized leukotrienes, is a major cause for inducing several diseases such as chronic inflammation, rheumatic arthritis, allergy, asthma and psoriasis. When the cell content of leukotriene becomes increased, tissue and organ are acutly and chronically damaged by bacterial infection and an endotoxin generated thereby as well as inflammatory cells are activated, which then results in development of inflammatory diseases such as chronic inflammation and rheumatis.
Therefore, by developming a 5-LO inhibitor capable of preventing tissue and organ damages by inhibiting the activiation of inflammatory cells due to the increase in cellular leukotriene, it is made possible to prevent or treat several diseases caused by inflammation.
Since a natural product and synthetic compound having a benzopyran backbone show an antioxidant activity, they have been widely known as a privileged structure for developing a pharmacological therapeutic compound effective for treating nervous diseases, hypertension and diabetes and broadly employed in a medicinal chemistry field. However, there is no report that a compound having a benzopyran moiety as a privileged structure is developed as a therapeutic agent for an inflammatory disease.
Meanwhile, the construction of a benzopyran library having various derivatives using a combinatorial chemical synthetic method can be effectively used for screening a hit compound and lead compound at the early stage of a new drug development.
Particularly, it is very important to efficiently construct a large and focused library of small organic molecule, which is capable of introducing various derivatives within a molecule and does not significantly deviate from the range of Rule of 5 by Lipinsky, by using a combinatorial chemical synthetic method for securing molecular variety effective for the screening of a lead compound.
A combinatorial chemistry is a new synthetic thechnique for developing a new compound. While the conventional organic synthetic techniques can synthesize one kind of compound via a single reaction, the combinatorial chemical synthetic technique is highly efficient which can synthesize more various and numerous compounds at the same time or automatize the multi-step synthetic process. It has been easier to screen a hit compound and lead compound having a new structure and optimize their structure and activity due to the introduction of the combinatorial chemical synthetic method.
Further, the combinatorial chemical synthetic method carries out most reaction procedures on a solid support, which makes possible to automatize a successive multi-step reaction (and reaction procedure), and is capable of performing a high throughput screening (HTS) because it is very simple to purify final products.
Although the combinatorial chemical synthetic method solves the uneconomical and unefficient problems of the conventional synthetic methods, there are several reasons why this method does not be easily applied to an organic synthetic field. One representative reason among them is to cause an undesirable side-reaction because most chemical reactions carried on a solid support and used the excessive amount of reaction agents, and the other is to limit an employable solvent depending on the physical property of solid support, which makes narrow the range of chemical reaction to be selected. It has been widely employed Merrifield resin and Wang resin as the solid support in the combinatorial chemical synthesis. Since these solid supports show a significantly low swelling effect in high polar solvents such as alcohols and water, it is very restricted to select a solvent nessesary for the reaction. Accordingly, in order to synthesize various derivatives using solid-phase reaction, there is a need of selecting a solid support and linker, the examination of a reagent and reaction condition, and the selection of substituent group capable of diversly changing the chemical structure and physical property of a target compound. Consequently, for the construction of a target compound library using solid-phase synthesis, it has to be efficiently developed a reaction condition suitable for the characteristics of a target compound and a treatment procedure after a reaction.
The present inventors have found that 6-alkylamino benzopyran derivative significantly inhibits 5-LO activity. Further, the present inventors have endeavored to develop an optimized technique for screening a lead compound by constructing a library of 6-alkylamino benzopyran derivatives on solid-phase using a combinatorial chemical synthetic method. As a result, the conventional chemical reaction on solution-phase synthesizes a target compound by carrying out each reaction step for introducing a subtituent group, a purification step after the reaction and a structural confirmation test, while in oreder to synthesize a target compound library having various substituents using a solid-phase parallel synthesis, the present inventors have performed several reactions at the same time and an efficient treatment procedure after the reaction, to economically produce 6-alkylamino-2,2-disubstituted-7,8-disubstituted-2H-1-benzopyran library in a short period with high yields.